We performed bidirectional, two-sample MR between our meta-analysis results for depression and all available traits which had a significant genetic correlation with depression (identified in the previous section). Traits directly related to or including depression (major depressive disorder, depressive symptoms and PGC cross disorder) were excluded due to potential bias. The genetic instruments for depression consisted of the independent, genome-wide significant variants, their effect sizes and standard errors, as estimated in our genome-wide meta-analysis. Summary statistics from genome-wide association studies for the other traits were sourced from either publicly available datasets or from the MR-Base database 11. Overlapping datasets for the exposure and the outcome can lead to bias and inflation of causal estimates 68. To mitigate this, when the source of the other trait included UK Biobank, 23andMe or any of the studies that contributed to PGC_139k, these studies were removed from our meta-analysis of depression; for example, the neuroticism trait from van den Berg, et al. 69 was assessed against a meta-analysis of depression using UK Biobank and 23andMe_307k only. Where UK Biobank, 23andMe and PGC_139k were all included in the genome-wide association study of the other trait then an alternative study was sought for that other trait.
